Erlotinib of Formula I, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) -4-quinazolinamine, is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen, and in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Erlotinib is administered as its hydrochloride salt and is currently marketed as TARCEVA® (erlotinib) tablets. Erlotinib hydrochloride has the molecular formula C22H23N3O4.HCl and a molecular weight of 429.90. It is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.
European Patent No. EP 0 817 775 (herein after “the '775 patent”) provides a process for the preparation of erlotinib, which involves adding 3-ethynylaniline and 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline in isopropanol containing pyridine, and then refluxing the mixture for 4 hours under the atmosphere of dry nitrogen. The solvent is removed and residue is extracted in 10% methanol in chloroform and saturated aqueous sodium bicarbonate. N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine base is separated chromatographically and converted to the hydrochloride salt in a solvent, such as, chloroform using hydrochloric acid. Though the '775 patent mentions few erlotinib acid-addition salt, for example, erlotinib salt with an inorganic or organic acid, such as, hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid, it only exemplifies the process for the preparation of erlotinib hydrochloride.
European Patent No. EP 1 044 969 provides a process for preparing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine which involves stirring 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol with anhydrous sodium hydroxide and 2-methoxyethanol and heating at reflux for 47 hours. The reaction mixture is cooled to 20° C. to 25° C. and concentrated hydrochloric acid is added to it. The resulting mixture is granulated at 20° C. to 25° C. to crystallize the product.
PCT Publication No. WO 2008/122776 A2 (herein after “the WO '776 application”) provides a process for the preparation of erlotinib salts, such as, erlotinib hydrochloride, erlotinib sulphate, erlotinib tosylate and erlotinib oxalate by reacting 4-halo-6,7-bis(2-methoxyethoxy)quinazoline with 3-aminophenyl acetylene or an acid salt thereof under acidic conditions to give corresponding acid salt of erlotinib.
PCT Publication WO 2007/138612 provides a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride which involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde. The 3,4-bis(2-methoxyethoxy)benzaldehyde is converted to 3,4-bis(2-methoxyethoxy)benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy)benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to obtain 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile. N′-(3-ethynylphenyl)-N,N-dimethyl formamidine obtained by formylation of 3-ethynylaniline with N,N-dimethyl formamidine is coupled with 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile to obtain erlotinib free base which upon treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
PCT Publication WO 2007/138613 provides a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride which involves reacting 3,4-dihydroxy benzaldehyde with substituted ethylmethyl ether in the presence of an inert solvent and base to obtain 3,4-bis(2-methoxyethoxy)benzaldehyde. The 3,4-bis(2-methoxyethoxy)benzaldehyde is converted to 3,4-bis(2-methoxyethoxy)benzaldoxime in the presence of a base and organic solvent and is further dehydrated to 3,4-bis(2-methoxyethoxy)benzonitrile. The benzonitrile so obtained is nitrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile which is further reduced to get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile. 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile is formylated with N,N-dimethyl formamidine to obtain N′-[2-cyano-4,5-bis(2-methoxyethoxy)phenyl]-N,N-dimethylformamidine which is coupled with an 3-ethynylaniline to obtain erlotinib free base which on treatment with a polar solvent containing hydrochloric acid gives erlotinib hydrochloride.
J. Chem. Soc., Perkin Trans. 2, 2000, 2498-2502 provides process for the preparation of erlotinib mesylate by treating erlotinib hydrochloride in water-ethylacetate with 50% aqueous sodium hydroxide solution at 50° C. and separating organic layer, filtering through short pad of celite, the resulting solution is warmed to 50° C. to redissolve precipitated free base, followed by treating the solution with methane sulphonic acid to give a white precipitate, which upon cooling for 4 hours gives erlotinib methane sulphonate.
Several processes have been reported for the preparation of erlotinib or pharmaceutically acceptable salts and their polymorphs, for example, in U.S. Pat. Nos. 6,476,040 B1; 6,900,221 B1; 7,148,231 B2; U.S. Publication Nos. 2005/0130995; 2006/0154941; 2008/0167327 A1; 2008/0058355 A1; PCT Publication Nos. WO 99/55683; WO 2001/034574; WO 2003/066602 A1; WO 2004/072049; WO 2007/060691; WO 2008/000418 A2; WO 2008/012105; WO 2008/049645; WO 2008/102369; WO 2008/122776; WO 2009/002538; WO 2009/007984; WO 2009/024989; WO 2009/025873 A2; WO 2009/025876 A2.
Since erlotinib constitutes an important therapeutic agent, additional and improved ways of preparing erlotinib and its salts are of value to pharmaceutical science. Thus, there is a need in the development of a consistent and novel process for preparing erlotinib and its salts which is commercially viable, safer for handling, less time consuming and of greater purity.
The present inventors have found a process for the preparation of erlotinib or its pharmaceutically acceptable salt thereof, which involves preparing erlotinib or its pharmaceutically acceptable salt thereof directly from 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile and avoiding the usage of corrosive chemicals, such as, phosphorus oxychloride/thionyl chloride. The present inventors also found a process for the preparation of erlotinib trifluoroacetate.
The present inventors have also found that erlotinib hydrochloride can be easily prepared in high purity directly from erlotinib trifluoroacetate without the formation of erlotinib base. The present inventors have also prepared erlotinib trifluoroacetate in a novel polymorphic form, designated as Form E. The novel polymorphic Form E of erlotinib trifluoroacetate of the present invention is suitable for preparing pharmaceutical compositions comprising erlotinib trifluoroacetate.